Mood and Anxiety Disorders and Suicidality in Patients With Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity.

BACKGROUND AND OBJECTIVES: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.

BACKGROUND AND OBJECTIVES: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants. METHODS: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models. RESULTS: Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses. DISCUSSION: Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.

Association of depression and COVID-induced PTSD with cognitive symptoms after COVID-19 illness.

OBJECTIVE: Many patients recovering from COVID-19 report persistent psychological and cognitive symptoms months after viral clearance. We examined the association of depression and COVID-induced PTSD with cognitive symptoms following COVID-19 illness. METHODS: Patients treated for COVID-19 between March 26 and May 27, 2020 were surveyed three months later. Cognitive symptoms were assessed by asking "Since your COVID-19 illness, do you now have more difficulty: 1) Remembering conversations a few days later? 2) Remembering where you placed familiar objects? 3) Finding the right words while speaking?" Patients endorsing at least one such complaint were coded positive for cognitive symptoms. Logistic regression was used to estimate the association of depression (PHQ-8 ≥ 10) and COVID-induced PTSD (PCL-5 ≥ 30) with cognitive symptoms, adjusting for demographic and clinical factors. RESULTS: Among 153 participants, 44.4% reported at least one cognitive symptom, 18.3% were depressed, and 23.5% had COVID-induced PTSD. Adjusting for covariates, depression (OR 5.15, 95% CI 1.30-20.35, p = 0.02) and COVID-induced PTSD (OR 3.67, 95% CI 1.13-11.89, p = 0.03) were significantly associated with cognitive symptoms; self-reported history of mental illness was also associated (OR 4.90, 95% CI 1.24-19.41, p = 0.02). CONCLUSIONS: Depression, COVID-induced PTSD, and prior mental illness were strongly associated with cognitive symptoms three months after acute COVID-19 illness.

Reproductive decision-making in families containing multiple individuals with epilepsy.

OBJECTIVE: This study evaluated factors influencing reproductive decision-making in families containing multiple individuals with epilepsy. METHODS: One hundred forty-nine adults with epilepsy and 149 adult biological relatives without epilepsy from families containing multiple affected individuals completed a self-administered questionnaire. Participants answered questions regarding their belief in a genetic cause of epilepsy (genetic attribution) and estimated risk of epilepsy in offspring of an affected person. Participants rated factors for their influence on their reproductive plans, with responses ranging from "much more likely" to "much less likely" to want to have a child. Those with epilepsy were asked, "Do you think you would have wanted more (or any) children if you had not had epilepsy?" RESULTS: Participants with epilepsy had fewer offspring than their unaffected relatives (mean = 1.2 vs. 1.9, p = .002), and this difference persisted among persons who had been married. Estimates of risk of epilepsy in offspring of an affected parent were higher among participants with epilepsy than among relatives without epilepsy (mean = 27.2 vs. 19.6, p = .002). Nineteen percent of participants with epilepsy responded that they would have wanted more children if they had not had epilepsy. Twenty-five percent of participants with epilepsy responded that "the chance of having a child with epilepsy" or "having epilepsy in your family" made them less likely to want to have a child. Having these genetic concerns was significantly associated with greater genetic attribution and estimated risk of epilepsy in offspring of an affected parent. SIGNIFICANCE: People with epilepsy have fewer children than their biological relatives without epilepsy. Beliefs about genetic causes of epilepsy contribute to concerns and decisions to limit childbearing. These beliefs should be addressed in genetic counseling to ensure that true risks to offspring and reproductive options are well understood.

Familial aggregation of status epilepticus in generalized and focal epilepsies.

OBJECTIVE: To determine whether familial aggregation of status epilepticus (SE) occurs in a large cohort of familial common epilepsies. METHODS: We used the Epilepsy Phenome/Genome Project dataset, which consisted of 2,197 participants in 1,043 family units with ≥2 members having a common generalized or nonacquired focal epilepsy (NAFE). We identified participants with a history of traditionally defined SE (TSE) (seizures ≥30 minutes) and operationally defined SE (OSE) (seizures ≥10 minutes) by chart review. We assessed familial aggregation of TSE and OSE using χ2 analysis and generalized estimating equations (GEE). RESULTS: One hundred fifty-five (7%) participants in 1,043 families had ≥1 episodes of TSE. Two hundred fifty (11%) had ≥1 episodes of OSE. In a χ2 analysis, the number of family units with ≥2 members having TSE (odds ratio [OR] 4.79, 95% confidence interval [CI] 2.56-8.97) or OSE (OR 4.23, 95% CI 2.67-6.70) was greater than expected by chance. In GEE models adjusted for sex, broad epilepsy class (GE or NAFE), age at onset, and duration of epilepsy, TSE in a proband predicted TSE in a first-degree relative (OR 2.79, 95% CI 1.24-6.22), and OSE in a proband predicted OSE in a first-degree relative (OR 2.91, 95% CI 1.65-5.15). The results remained significant in models addressing epilepsy severity by incorporating the number of antiseizure medications used or epilepsy surgery. CONCLUSIONS: TSE and OSE showed robust familial aggregation in a cohort of familial epilepsy independently of epilepsy severity or class, suggesting that genetic factors contribute to SE independently of the genetic cause of these epilepsies. CLINICALTRIALSGOV IDENTIFIER: NCT00552045.

Genetic attribution and perceived impact of epilepsy in multiplex epilepsy families.

OBJECTIVE: Studies have found that affected individuals who believe the cause of their disorder is genetic may react in various ways, including optimism for improved treatments and pessimism due to perceived permanence of the condition. This study assessed the psychosocial impact of genetic attribution among people with epilepsy. METHODS: Study participants were 165 persons with epilepsy from multiplex epilepsy families who completed a self-administered survey. Psychosocial impact of epilepsy was assessed with the Impact of Epilepsy Scale, containing items about relationships, employment, overall health, self-esteem, and standard of living. Genetic attribution was assessed using a scale derived from three items asking about the role of genetics in causing epilepsy in the family, the chance of having an epilepsy-related mutation, and the influence of genetics in causing the participant's epilepsy. We estimated prevalence ratios (PRs) for impact of epilepsy above the median using Poisson regression with robust standard errors, adjusting for number of lifetime seizures and time since last seizure. RESULTS: Participants' age averaged 51 years; 87% were non-Hispanic white, 63% were women, and 54% were college graduates. The genetic attribution scale was significantly associated with having a high impact of epilepsy (adjusted PR = 1.4, 95% confidence interval = 1.07-1.91, P = .02). One of the three genetic attribution questions was also significantly associated with a high impact of epilepsy (belief that genetics had a big role in causing epilepsy in the family, adjusted PR = 1.8). SIGNIFICANCE: These findings reflect an association between the psychosocial impact of epilepsy and the belief that epilepsy has a genetic cause, among people with epilepsy in families containing multiple affected individuals. This association could arise either because belief in a genetic cause leads to increased psychosocial impacts, or because a greater psychosocial impact of epilepsy leads some to believe their epilepsy is genetic.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

OBJECTIVE: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. INTERPRETATION: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

Familial aggregation of focal seizure semiology in the Epilepsy Phenome/Genome Project.

OBJECTIVE: To improve phenotype definition in genetic studies of epilepsy, we assessed the familial aggregation of focal seizure types and of specific seizure symptoms within the focal epilepsies in families from the Epilepsy Phenome/Genome Project. METHODS: We studied 302 individuals with nonacquired focal epilepsy from 149 families. Familial aggregation was assessed by logistic regression analysis of relatives' traits (dependent variable) by probands' traits (independent variable), estimating the odds ratio for each symptom in a relative given presence vs absence of the symptom in the proband. RESULTS: In families containing multiple individuals with nonacquired focal epilepsy, we found significant evidence for familial aggregation of ictal motor, autonomic, psychic, and aphasic symptoms. Within these categories, ictal whole body posturing, diaphoresis, dyspnea, fear/anxiety, and déjà vu/jamais vu showed significant familial aggregation. Focal seizure type aggregated as well, including complex partial, simple partial, and secondarily generalized tonic-clonic seizures. CONCLUSION: Our results provide insight into genotype-phenotype correlation in the nonacquired focal epilepsies and a framework for identifying subgroups of patients likely to share susceptibility genes.

Depression and genetic causal attribution of epilepsy in multiplex epilepsy families.

OBJECTIVES: Rapid advances in genetic research and increased use of genetic testing have increased the emphasis on genetic causes of epilepsy in patient encounters. Research in other disorders suggests that genetic causal attributions can influence patients' psychological responses and coping strategies, but little is known about how epilepsy patients and their relatives will respond to genetic attributions of epilepsy. We investigated the possibility that among members of families containing multiple individuals with epilepsy, depression, the most frequent psychiatric comorbidity in the epilepsies, might be related to the perception that epilepsy has a genetic cause. METHODS: A self-administered survey was completed by 417 individuals in 104 families averaging 4 individuals with epilepsy per family. Current depression was measured with the Patient Health Questionnaire. Genetic causal attribution was assessed by three questions addressing the following: perceived likelihood of having an epilepsy-related mutation, perceived role of genetics in causing epilepsy in the family, and (in individuals with epilepsy) perceived influence of genetics in causing the individual's epilepsy. Relatives without epilepsy were asked about their perceived chance of developing epilepsy in the future, compared with the average person. RESULTS: Prevalence of current depression was 14.8% in 182 individuals with epilepsy, 6.5% in 184 biologic relatives without epilepsy, and 3.9% in 51 individuals married into the families. Among individuals with epilepsy, depression was unrelated to genetic attribution. Among biologic relatives without epilepsy, however, prevalence of depression increased with increasing perceived chance of having an epilepsy-related mutation (p = 0.02). This association was not mediated by perceived future epilepsy risk among relatives without epilepsy. SIGNIFICANCE: Depression is associated with perceived likelihood of carrying an epilepsy-related mutation among individuals without epilepsy in families containing multiple affected individuals. This association should be considered when addressing mental health issues in such families.

Genetic effects on sleep/wake variation of seizures.

OBJECTIVE: There is a complex bidirectional relationship between sleep and epilepsy. Sleep/wake timing of seizures has been investigated for several individual seizure types and syndromes, but few large-scale studies of the timing of seizures exist in people with varied epilepsy types. In addition, the genetic contributions to seizure timing have not been well studied. METHODS: Sleep/wake timing of seizures was determined for 1,395 subjects in 546 families enrolled in the Epilepsy Phenome/Genome Project (EPGP). We examined seizure timing among subjects with different epilepsy types, seizure types, epilepsy syndromes, and localization. We also examined the familial aggregation of sleep/wake occurrence of seizures. RESULTS: Seizures in nonacquired focal epilepsy (NAFE) were more likely to occur during sleep than seizures in generalized epilepsy (GE), for both convulsive (odds ratio [OR] 5.2, 95% confidence interval [CI] 3.59-7.52) and nonconvulsive seizures (OR 4.2, 95% CI 2.48-7.21). Seizures occurring within 1 h of awakening were more likely to occur in patients with GE than with NAFE for both convulsive (OR 2.3, 95% CI 1.54-3.39) and nonconvulsive (OR 1.7, 95% CI 1.04-2.66) seizures. Frontal onset seizures were more likely than temporal onset seizures to occur during sleep. Sleep/wake timing of seizures in first-degree relatives predicted timing of seizures in the proband. SIGNIFICANCE: We found that sleep/wake timing of seizures is associated with both epilepsy syndrome and seizure type. In addition, we provide the first evidence for a genetic contribution to sleep/wake timing of seizures in a large group of individuals with common epilepsy syndromes.

Parents' interest in genetic testing of their offspring in multiplex epilepsy families.

OBJECTIVE: To evaluate parents' interest in genetic testing of their offspring in families containing multiple individuals with epilepsy. METHODS: Seventy-seven parents with affected offspring and 173 parents without affected offspring from families containing multiple individuals with epilepsy completed a questionnaire asking about their interest in genetic testing of their offspring. Interest in testing was ascertained in four scenarios defined by clinical utility and penetrance of the gene in the test (100% vs. 50%). Pairwise agreement in interest was assessed between parents for testing themselves versus their offspring, and between mothers and fathers for their offspring. RESULTS: Among parents with affected offspring, the proportion interested in genetic testing of offspring ("diagnostic testing") was 86% in the 100% penetrance, clinical utility scenario, and 71% in the 100% penetrance, no clinical utility scenario (p = 0.007). Among parents without affected offspring, comparable proportions interested in genetic testing of offspring ("predictive testing") were 74% and 53% (p < 0.001), and were significantly lower than in parents with affected offspring (clinical utility, p = 0.02; no clinical utility, p = 0.01). Interest in testing did not differ by gene penetrance. Parents' agreement in testing interest for themselves versus their offspring was "substantial" (90% agreement, κ = 0.72) for a test with clinical utility, and "almost perfect" for a test without clinical utility (94% agreement, κ = 0.88). Agreement in testing interest between mothers and fathers was "moderate" for a test with clinical utility (85% agreement, κ = 0.48,), and "fair" for a test without clinical utility (67% agreement, κ = 0.30). SIGNIFICANCE: Interest in diagnostic genetic testing is strong among parents with offspring with epilepsy, particularly when the test offers clinical utility. Testing interest is lower for a diagnostic test without clinical utility, or for a predictive test in offspring at risk of developing epilepsy in the future.

Genetic causal attribution of epilepsy and its implications for felt stigma.

OBJECTIVE: Research in other disorders suggests that genetic causal attribution of epilepsy might be associated with increased stigma. We investigated this hypothesis in a unique sample of families containing multiple individuals with epilepsy. METHODS: One hundred eighty-one people with epilepsy and 178 biologic relatives without epilepsy completed a self-administered survey. In people with epilepsy, felt stigma was assessed through the Epilepsy Stigma Scale (ESS), scored 1-7, with higher scores indicating more stigma and >4 indicating some felt stigma. Felt stigma related to having epilepsy in the family was assessed through the Family Epilepsy Stigma Scale (FESS), created by replacing "epilepsy" with "epilepsy in my family" in each ESS item. Genetic attribution was assessed through participants' perceptions of the (1) role of genetics in causing epilepsy in the family, (2) chance they had an epilepsy-related mutation, and (3) (in people with epilepsy) influence of genetics in causing their epilepsy. RESULTS: Among people with epilepsy, 22% met criteria for felt stigma (ESS score >4). Scores were increased among individuals who were aged ≥60 years, were unemployed, reported epilepsy-related discrimination, or had seizures within the last year or >100 seizures in their lifetime. Adjusting for other variables, ESS scores in people with epilepsy were significantly higher among those who perceived genetics played a "medium" or "big" role in causing epilepsy in the family than in others (3.4 vs. 2.7, p = 0.025). Only 4% of relatives without epilepsy had felt stigma. Scores in relatives were unrelated to genetic attribution. SIGNIFICANCE: In these unusual families, predictors of felt stigma in individuals with epilepsy are similar to those in other studies, and stigma levels are low in relatives without epilepsy. Felt stigma may be increased in people with epilepsy who believe epilepsy in the family has a genetic cause, emphasizing the need for sensitive communication about genetics.

Genetic testing preferences in families containing multiple individuals with epilepsy.

OBJECTIVE: To examine genetic testing preferences in families containing multiple individuals with epilepsy. METHODS: One hundred forty-three individuals with epilepsy and 165 biologic relatives without epilepsy from families containing multiple affected individuals were surveyed using a self-administered questionnaire. Four genetic testing scenarios were presented, defined by penetrance (100% vs. 50%) and presence or absence of clinical utility. Potential predictors of genetic testing preferences were evaluated using generalized estimating equations with robust Poisson regression models. The influence of 21 potential testing motivations was also assessed. RESULTS: For the scenario with 100% penetrance and clinical utility, 85% of individuals with epilepsy and 74% of unaffected relatives responded that they would definitely or probably want genetic testing. For the scenario with 100% penetrance but without clinical utility, the proportions who responded that they would want testing were significantly lower in both affected individuals (69%) and unaffected relatives (57%). Penetrance (100% vs. 50%) was not a significant predictor of genetic testing interest. The highest-ranking motivations for genetic testing were the following: the possibility that the results could improve health or health care, the potential to know if epilepsy in the family is caused by a gene, and the possibility of changing behavior or lifestyle to prevent seizures. SIGNIFICANCE: Interest in epilepsy genetic testing may be high in affected and unaffected individuals in families containing multiple individuals with epilepsy, especially when testing has implications for improving clinical care.

Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy.

Many symptoms of neurologic or psychiatric illness--such as cognitive impairment, depression, anxiety, attention deficits, and migraine--occur more frequently in people with epilepsy than in the general population. These diverse comorbidities present an underappreciated problem for people with epilepsy and their caregivers because they decrease quality of life, complicate treatment, and increase mortality. In fact, it has been suggested that comorbidities can have a greater effect on quality of life in people with epilepsy than the seizures themselves. There is increasing recognition of the frequency and impact of cognitive and behavioral comorbidities of epilepsy, highlighted in the 2012 Institute of Medicine report on epilepsy. Comorbidities have also been acknowledged, as a National Institutes of Health (NIH) Benchmark area for research in epilepsy. However, relatively little progress has been made in developing new therapies directed specifically at comorbidities. On the other hand, there have been many advances in understanding underlying mechanisms. These advances have made it possible to identify novel targets for therapy and prevention. As part of the International League Against Epilepsy/American Epilepsy Society workshop on preclinical therapy development for epilepsy, our working group considered the current state of understanding related to terminology, models, and strategies for therapy development for the comorbidities of epilepsy. Herein we summarize our findings and suggest ways to accelerate development of new therapies. We also consider important issues to improve research including those related to methodology, nonpharmacologic therapies, biomarkers, and infrastructure.

Glyoxalase 1 and its substrate methylglyoxal are novel regulators of seizure susceptibility.

PURPOSE: Epilepsy is a complex disease characterized by a predisposition toward seizures. There are numerous barriers to the successful treatment of epilepsy. For instance, current antiepileptic drugs have adverse side effects and variable efficacies. Furthermore, the pathophysiologic basis of epilepsy remains largely elusive. Therefore, investigating novel genes and biologic processes underlying epilepsy may provide valuable insight and enable the development of new therapeutic agents. We previously identified methylglyoxal (MG) as an endogenous γ-aminobutyric acid (GABAA ) receptor agonist. Here, we investigated the role of MG and its catabolic enzyme, glyoxalase 1 (GLO1), in seizures. METHODS: We pretreated mice with MG before seizure induction with picrotoxin or pilocarpine and then assessed seizures behaviorally or by electroencephalography (EEG). We then investigated the role of GLO1 in seizures by treating mice with a pharmacologic inhibitor of GLO1 before seizure induction with pilocarpine and measured subsequent seizure phenotypes. Next, we explored the genetic relationship between Glo1 expression and seizures. We analyzed seizure phenotypes among C57BL/6J × DBA/2J (BXD) recombinant inbred (RI) mice with differential Glo1 expression. Lastly, we investigated a causal role for Glo1 in seizures by administering pilocarpine to transgenic (Tg) mice that overexpress Glo1. KEY FINDINGS: Pretreatment with MG attenuated pharmacologically-induced seizures at both the behavioral and EEG levels. GLO1 inhibition, which increases MG concentration in vivo, also attenuated seizures. Among BXD RI mice, high Glo1 expression was correlated with increased seizure susceptibility. Tg mice overexpressing Glo1 displayed reduced MG concentration in the brain and increased seizure severity. SIGNIFICANCE: These data identify MG as an endogenous regulator of seizures. Similarly, inhibition of GLO1 attenuates seizures, suggesting that this may be a novel therapeutic approach for epilepsy. Furthermore, this system may represent an endogenous negative feedback loop whereby high metabolic activity increases inhibitory tone via local accumulation of MG. Finally, Glo1 may contribute to the genetic architecture of epilepsy, as Glo1 expression regulates both MG concentration and seizure severity.

Evidence for a shared genetic susceptibility to migraine and epilepsy.

PURPOSE: Although epilepsy and migraine are known to co-occur within individuals, the contribution of a shared genetic susceptibility to this comorbidity remains unclear. We investigated the hypothesis of shared genetic effects on migraine and epilepsy in the Epilepsy Phenome/Genome Project (EPGP) cohort. METHODS: We studied prevalence of a history of migraine in 730 EPGP participants aged ≥ 12 years with nonacquired focal epilepsy (NAFE) or generalized epilepsy (GE) from 501 families containing two or more individuals with epilepsy of unknown cause. Information on migraine without aura (MO) and migraine with aura (MA) was collected using an instrument validated for individuals ≥ 12 years. Because many individuals have both MO and MA, we considered two nonoverlapping groups of individuals with migraine: those who met criteria for MA in any of their headaches (MA), and those who did not ("MO-only"). EPGP participants were interviewed about the history of seizure disorders in additional nonenrolled family members. We evaluated associations of migraine prevalence in enrolled subjects with a family history of seizure disorders in additional nonenrolled relatives, using generalized estimating equations to control for the nonindependence of observations within families. KEY FINDINGS: Prevalence of a history of MA (but not MO-only) was significantly increased in enrolled participants with two or more additional affected first-degree relatives. SIGNIFICANCE: These findings support the hypothesis of a shared genetic susceptibility to epilepsy and MA.

Recruitment for genetic studies of epilepsy.

Virtually nothing has been published about recruitment of adults with sporadic temporal lobe epilepsy (TLE) for genetic studies. We examined eligibility, recruitment, participation rates, and reasons for exclusion in a genetic study of TLE. Participants with non-acquired TLE with onset ≤35 were recruited through review of records and screening of incoming patients at Columbia University Medical Center (CUMC). Eligible patients were asked to participate in an interview about seizures and give a blood sample for DNA extraction. Medical records were sought for each participant. Of 2974 patients screened 252 (8.5%) were eligible, and 40 (15.9% of eligible) participated. Leading reasons for ineligibility included an antecedent cause of epilepsy, syndrome other than TLE, and seizure onset after age 35. Those declining participation cited concerns about confidentiality, lack of compensation, and fear of phlebotomy. Although TLE is common and patients were recruited from a major surgical epilepsy center, a small proportion of potential participants participated. Large numbers need to be screened to reach the target sample size. Obtaining permission from treating physicians to contact their patients directly can improve recruitment. Saliva DNA collection, monetary incentives and patient education can improve participation. This information can facilitate study design in epilepsy genetics.

Mapping a mouse limbic seizure susceptibility locus on chromosome 10.

PURPOSE: Mapping seizure susceptibility loci in mice provides a framework for identifying potentially novel candidate genes for human epilepsy. Using C57BL/6J × A/J chromosome substitution strains (CSS), we previously identified a locus on mouse chromosome 10 (Ch10) conferring susceptibility to pilocarpine, a muscarinic cholinergic agonist that models human temporal lobe epilepsy by inducing initial limbic seizures and status epilepticus (status), followed by hippocampal cell loss and delayed-onset chronic spontaneous limbic seizures. Herein we report further genetic mapping of pilocarpine quantitative trait loci (QTLs) on Ch10. METHODS: Seventy-nine Ch10 F(2) mice were used to map QTLs for duration of partial status epilepticus and the highest stage reached in response to pilocarpine. Based on those results we created interval-specific congenic lines to confirm and extend the results, using sequential rounds of breeding selectively by genotype to isolate segments of A/J Ch10 genome on a B6 background. KEY FINDINGS: Analysis of Ch10 F(2) genotypes and seizure susceptibility phenotypes identified significant, overlapping QTLs for duration of partial status and severity of pilocarpine-induced seizures on distal Ch10. Interval-specific Ch10 congenics containing the susceptibility locus on distal Ch10 also demonstrated susceptibility to pilocarpine-induced seizures, confirming results from the F(2) mapping population and strongly supporting the presence of a QTL between rs13480781 (117.6 Mb) and rs13480832 (127.7 Mb). SIGNIFICANCE: QTL mapping can identify loci that make a quantitative contribution to a trait, and eventually identify the causative DNA-sequence polymorphisms. We have mapped a locus on mouse Ch10 for pilocarpine-induced limbic seizures. Novel candidate genes identified in mice can be investigated in functional studies and tested for their role in human epilepsy.